RESUMO
Idiopathic pulmonary fibrosis (IPF) is a chronic lung disease characterized by parenchymal scarring, leading progressively to alveolar architecture distortion, respiratory failure, and eventually death. Currently, there is no effective treatment for IPF. Previously, 3'5-dimaleamylbenzoic acid (3'5-DMBA), a maleimide, demonstrated pro-apoptotic, anti-inflammatory, and anti-cancer properties; however, its potential therapeutic effects on IPF have not been addressed. Bleomycin (BLM) 100 U/kg was administered to CD1 mice through an osmotic minipump. After fourteen days of BLM administration, 3'5-DMBA (6 mg/kg or 10 mg/kg) and its vehicle carboxymethylcellulose (CMC) were administered intragastrically every two days until day 26. On day 28, all mice were euthanized. The 3'5-DMBA effect was assessed by histological and immunohistochemical staining, as well as by RT-qPCR. The redox status on lung tissue was evaluated by determining the glutathione content and the GSH/GSSG ratio. 3'5-DMBA treatment re-established typical lung histological features and decreased the expression of BLM-induced fibrotic markers: collagen, α-SMA, and TGF-ß1. Furthermore, 3'5-DMBA significantly reduced the expression of genes involved in fibrogenesis. In addition, it decreased reduced glutathione and increased oxidized glutathione content without promoting oxidative damage to lipids, as evidenced by the decrease in the lipid peroxidation marker 4-HNE. Therefore, 3'5-DMBA may be a promising candidate for IPF treatment.
Assuntos
Bleomicina , Fibrose Pulmonar Idiopática , Animais , Anti-Inflamatórios/farmacologia , Bleomicina/efeitos adversos , Colágeno/metabolismo , Fibrose Pulmonar Idiopática/induzido quimicamente , Fibrose Pulmonar Idiopática/tratamento farmacológico , Fibrose Pulmonar Idiopática/metabolismo , Pulmão/patologia , Camundongos , Camundongos Endogâmicos C57BL , Fator de Crescimento Transformador beta1/metabolismoRESUMO
To evaluate the association between TGFB1 + 869 T > C (rs1800470) and TGFB1-509 C > T (rs1800469) variants with susceptibility for rheumatoid arthritis (RA), disease activity, presence of rheumatoid factor (RF), anti-cyclic citrullinated peptide (anti-CCP) and TGF-ß1 plasma levels. A total of 262 patients with RA and 168 control individuals were tested for the TGFB1 variants using a TaqMan genotyping assay. Disease activity score in 28 joints (DAS28) classified RA patients into two groups of disease activity: remission/mild (DAS28 < 3.2) and moderate/severe (DAS28 ≥ 3.2). TGFB1 + 869 T > C and -509 C > T variants, independently or in haplotype combination, were not associated with RA's susceptibility. Patients with the TGFB1-509 TT genotype had a higher frequency of DAS28 ≥ 3.2 (OR 2.58, 95% CI 1.04-6.42, p = 0.041). The TGFB1 + 869 CC genotype in seropositive patients for RF or anti-CCP was associated with decreased TGF-ß1 levels (p = 0.032 and p = 0.039, respectively). Patients with the TGFB1 + 869 C allele and elevated RF titles demonstrated a higher frequency of DAS28 ≥ 3.2 (p = 0.037). The TGFB1 + 869 T > C variant was associated with diminished TGF-ß1 plasma levels and moderate/severe activity disease only in seropositive RF patients. This is the first study showing that TGF-ß1 plasma levels can be modulated by the interaction between the TGFB1 + 869 T > C variant and autoantibodies. However, the TGFB1-509 C > T variant was associated with moderate/severe activity disease, independently of autoantibodies positivity. Thus, our findings suggest that TGFB1 + 869 T > C and -509 C > T variants can predict activity disease in different RA patient subgroups.
Assuntos
Artrite Reumatoide , Autoanticorpos , Alelos , Artrite Reumatoide/genética , Humanos , Fator Reumatoide/genética , Fator de Crescimento Transformador beta1/genéticaRESUMO
Environmental hexachlorobenzene (HCB) increases blood pressure (BP) in female rats, causing alterations in arterial structure and function. Here we study the role of Angiotensin II receptor type 1 (AT1) in HCB-induced hypertension through the use of AT1 antagonist losartan. HCB-treated male rats showed a 22.7% increase in BP which was prevented by losartan. Losartan blocked HCB-induced changes in arterial morphology (decreased aorta cell number and increased wall thickness). Losartan also prevented HCB-induced alterations in artery relaxation by acetylcholine and nitroprusside but not the reduction in the maximum contraction by phenylephrine. Losartan rescued arterial molecular alterations caused by HCB (i.e. an increase in TGF-ß1 and AT1 expression and a decrease in eNOS expression and nitrite levels) and reduced hydrogen sulfide plasma concentration. In conclusion: in this work we demonstrate that AT1 activity is involved in HCB effects on the vascular system leading to hypertension.
RESUMO
BACKGROUND: The epiphyseal growth plate is an important anatomical segment localized on the ends of a long bone. Despite the abovementioned atractive reasons for alendronate's use, few data on the effect of alendronate during epiphyseal growth exist. AIM: Verify the effect of alendronate on the growth epiphyseal plate, and compare its effect with the size of the femur during the double-staining of the immunolocalization of transforming growth factor-ß1 (TGF-ß1) and bone morphogenetic protein-2 (BMP2) in endochondral ossifing in specimens that have received alendronate. METHODS: Forty newborn rats were randomly divided into two groups: a control group (were given applications of 1 mg/kg physiologic saline) and a group that received Alendronate (a dose of 2.5 mg/kg). These groups were then divided into two subgroups for euthanasia in two and 12 d of life. After euthanasia, the femurs were removed, and the femoral bones were measured linearly between the apex of the greater trochanter until the lower intercondylar midlle face to verify the probable bone growth between 3 and 12 d in control and alednroanto treated rats. Posteriorly, the surgical pieces were also sent to the histopathology laboratory to produce histological slides. The obtained slides were stained with hematoxylin and eosin to measure each of the cartilage zones in endochondral development. and other slides were immunohistochemically tested for anti- TGF-ß1 and BMP-2 antibodies to investigate the immunolocalization of these proteins in the epiphyseal plaque area. RESULTS: On the third day, some diferences between the control group and specimens treated with alendronate were verified. Macroscopiccaly, we found similarities in size between the femoral bones when we compared the control group with the specimens that received alendronate. On the 12th day, the bone size of the mice receiving the drug was significantly smaller than those of the control group. These results coincide with changes in the TGF-ß1 and BMP-2 expression. In the specimens that received alendronate, the TGF-ß1 was expressed in some sites of trabecular bone that was neoformed, peripherally to the bone marrow area. The BMP-2 was also positive in proliferative chondrocytes and hypertrofic chondrocytes. On the 12th day, all layers of chondrocytes exhibited positivity for BMP-2 in the specimens that received alendronate. In the interface between the trabecular bone and cartilage, an area of disorganized bone deposition was evident. Neoformed bone also appeared to be different at 12 d. In the control group, BMP-2 was positive in an intense area of bone trabeculae, whereas the alendronate-treated group showed TGF-ß1 positive trabeculae and a greater bone area. CONCLUSION: Alendronate alters the immunolocalization of TGF-ß1 and BMP-2 simultaneously, a condition that changes the usual histological aspects of the cartilage zone and impairs epiphysis growth and femur growth.
RESUMO
Obesity and aging lead to abnormal transforming growth factor-ß1 (TGF-ß1) signaling in the hypothalamus, triggering the imbalance on glucose metabolism and energy homeostasis. Here, we determine the effect of acute exercise on TGF-ß1 expression in the hypothalamus of two models of obesity in mice. The bioinformatics analysis was performed to evaluate the correlation between hypothalamic Tgf-ß1 messenger RNA (mRNA) and genes related to thermogenesis in the brown adipose tissue (BAT) by using a large panel of isogenic BXD mice. Thereafter, leptin-deficient (ob/ob) mice and obese C57BL/6 mice fed on a high-fat diet (HFD) were submitted to the acute exercise protocol. Transcriptomic analysis by using BXD mouse reference population database revealed that hypothalamic Tgf-ß1 mRNA is negatively correlated with genes related to thermogenesis in brown adipose tissue of BXD mice, such as peroxisome proliferator-activated receptor gamma coactivator and is positively correlated with respiratory exchange ratio. In agreement with these results, leptin-deficient (ob/ob) and HFD-fed mice displayed high levels of Tgf-ß1 mRNA in the hypothalamus and reduction of Pgc1α mRNA in BAT. Interestingly, an acute exercise session reduced TGF-ß1 expression in the hypothalamus, increased Pgc1α mRNA in the BAT and reduced food consumption in obese mice. Our results demonstrated that acute physical exercise suppressed hypothalamic TGF-ß1 expression, increasing Pgc1α mRNA in BAT in obese mice.
Assuntos
Regulação para Baixo , Hipotálamo/metabolismo , Obesidade/genética , Condicionamento Físico Animal/fisiologia , Fator de Crescimento Transformador beta1/genética , Tecido Adiposo Marrom/metabolismo , Animais , Dieta Hiperlipídica/efeitos adversos , Metabolismo Energético/genética , Perfilação da Expressão Gênica/métodos , Leptina/deficiência , Leptina/genética , Masculino , Camundongos Endogâmicos C57BL , Camundongos Obesos , Obesidade/etiologia , Obesidade/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/genética , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Termogênese/genética , Fator de Crescimento Transformador beta1/metabolismoRESUMO
OBJECTIVES: The purposes of this study were to evaluate a model of slow caries progression and to investigate the performance of a self-etch adhesive system for partial caries removal. MATERIALS AND METHODS: Rat molars were infected with Streptococcus sobrinus 6715 culture. Different time points were analyzed: days 78, 85, and 95 (± 2). After this, the samples were processed for morphological analysis. Additionally, the first molars were restored with zinc oxide and eugenol (IRM™; Dentsply; Brazil) or adhesive system (Clearfil SE Bond™; Kuraray Medical; Japan) 78 days after caries induction. After, 3 or 15 days post-treatment, the animals were euthanized, and their mandibles were processed for morphological analysis, classified by means of scores, and submitted to statistical analysis. Subsequently, immunohistochemical analysis was performed for osteonectin (OSN) and transforming growth factor-ß1 (TGF-ß1) expression. RESULTS: According to the caries induction model used, on day 95 greater inflammatory infiltration (p < 0.001), and more extensive degradation of secondary/primary dentin were demonstrated than on day 78 (p < 0.05). Furthermore, the restorative materials presented similar performance (p > 0.05) and proved to be fundamental to control the carious lesion. The TGF-ß1 and OSN were shown to be active during the caries process. CONCLUSIONS: The slow caries lesion model was feasible for morphological analysis of the dentin-pulp complex. The self-etch adhesive system triggered no acute inflammatory infiltration or pulp necrosis, instead it seemed to stimulate early pulp repair. CLINICAL RELEVANCE: Clearfil SE Bond™ applied directly on caries-affected dentin did not predispose to pulp inflammation; instead, it appeared to provide early biological benefits.
Assuntos
Cárie Dentária/terapia , Cimentos Dentários/farmacologia , Cimentos de Resina/farmacologia , Cimento de Óxido de Zinco e Eugenol/farmacologia , Condicionamento Ácido do Dente , Animais , Cárie Dentária/microbiologia , Modelos Animais de Doenças , Progressão da Doença , Imuno-Histoquímica , Masculino , Mandíbula , Dente Molar/microbiologia , Osteonectina/metabolismo , Ratos , Ratos Wistar , Streptococcus sobrinus , Propriedades de Superfície , Fator de Crescimento Transformador beta/metabolismoRESUMO
Alzheimer's disease is a neurodegenerative condition affecting millions of people worldwide. Alzheimer's symptoms include memory loss and cognitive decline. Pathologically, the hallmarks of Alzheimer´s are the presence of Amyloid beta-plaques, neurofibrillary tangles, and neuronal loss. Unfortunately, no cure is presently available and current treatments are only symptomatic. Transforming growth factor beta type I (TGF-ß1) is a trophic factor involved in neuronal development and synaptic plasticity. Impairment of TGF-ß1 signaling is associated with exacerbated Aß deposition and neurofibrillary tangle formation, which increases neurodegeneration. Aging and chronic inflammation reduce the canonical TGF-ß1/Smad signaling, facilitating cytotoxic activation of microglia and microgliamediated neurodegeneration This review gathers together evidence for a neuroprotective role of TGF-ß in Alzheimer's disease. Restoring TGF-ß1 signaling impairment may be a new pharmacological strategy Alzheimer's treatment.
Assuntos
Doença de Alzheimer/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Doença de Alzheimer/terapia , Peptídeos beta-Amiloides/metabolismo , Animais , Humanos , Inflamação Neurogênica/metabolismo , Fármacos Neuroprotetores/uso terapêutico , Receptor do Fator de Crescimento Transformador beta Tipo II/genética , Receptor do Fator de Crescimento Transformador beta Tipo II/metabolismo , Transdução de SinaisRESUMO
The aim of the present study was to establish the role of IL-6 and TGF-ß1 gene polymorphisms in the risk of developing in-stent restenosis. Two IL-6 [rs1800796 (-572 G>C), rs2069827 (-1426 T>G)] and two TGF-ß1 [rs1800469 (-509 T>C), rs1800470 (T29C)] gene polymorphisms were analyzed by 5' exonuclease TaqMan genotyping assays in a group of 244 patients, who underwent coronary artery stenting. Basal and procedure coronary angiography were analyzed, looking for angiographic predictors of restenosis and follow-up angiography was performed to screen for binary restenosis. Under the dominant and additive models adjusted for hypertension, stable angina, stent used, and diameter of stent, the TGF-ß1 T29C (rs1800470) polymorphism was significantly associated with an increase risk of restenosis when compared to patients without restenosis (OR=2.06, 95% CI: 1.03-4.11, P(Dom)=0.034 and OR=1.64, 95% CI: 1.09-2.45, PAdd=0.016). TGF-ß1 polymorphisms were in linkage disequilibrium and one haplotype (TT) was significantly increased in patients with restenosis when compared to patients without restenosis (OR=2.03, P=0.041). In summary, our results suggest that the TGF-ß1 T29C gene polymorphism could be involved in the risk of developing restenosis after coronary stent placement.
Assuntos
Biomarcadores/metabolismo , Doença da Artéria Coronariana/cirurgia , Reestenose Coronária/genética , Interleucina-6/genética , Polimorfismo Genético/genética , Complicações Pós-Operatórias , Stents , Fator de Crescimento Transformador beta1/genética , Idoso , Angiografia Coronária , Reestenose Coronária/metabolismo , Reestenose Coronária/patologia , Feminino , Seguimentos , Predisposição Genética para Doença , Genótipo , Humanos , Masculino , México , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , PrognósticoRESUMO
Silent myocardial ischemia (SMI) is a multifactorial and polygenic disorder that results from an excessive inflammatory response. Considering the prominent role of IL-10 and TGF-B1 as regulators of the inflammatory process and vascular physiology, the aim of the present study was to analyze whether IL-10 and TGF-B1 single nucleotide polymorphisms (SNPs) are associated with SMI. The IL-10-1082 A>G (rs1800896), IL-10-819 T>C (rs1800871), IL-10-592 A>C (rs1800872), TGF-ß1-509 T>C (rs1800469), and TGF-ß1 T29C (rs1800470) SNPs were analyzed by 5'exonuclease TaqMan genotyping assays in a group of 149 SMI patients and 248 healthy controls. The IL-10-1082 A>G (rs1800896) SNP was significantly associated with an increased risk of SMI as compared to controls under both dominant and heterozygous models (OR=1.77, Pdom=0.029 and OR=1.69, PHet=0.043). On the other hand, the TGF-ß1 509 T>C (rs1800469) SNP was significantly associated with increased risk of SMI as compared to controls under a dominant and additive models (OR=1.82, Pdom=0.035, OR=1.50, Padd=0.026). Finally, the TGF-ß1 T29C (rs1800470) SNP was significantly associated with increased risk of SMI as compared to controls under a co-dominant, dominant, recessive, and additive models (OR=3.63, PCod=0.004, OR=2.24, Pdom=0.002, OR=2.46, Prec=0.03 and OR=1.94, Padd=0.001). After adjusted for gender, age, and smoking, two haplotypes (CC and TT) were associated with decreased risk of SMI (OR=0.26, P<0.0001 and OR=0.15, P=0.017). In summary, our data suggest that the IL-10-1082 A>G (rs1800896), TGF-ß1-509 T>C (rs1800469), and TGF-ß1 T29C (rs1800470) SNPs play an important role in the risk of developing SMI. In our study, it was possible to distinguish two protective haplotypes in TGF-ß1 for SMI development.
Assuntos
Predisposição Genética para Doença/genética , Interleucina-10/genética , Isquemia Miocárdica/genética , Polimorfismo de Nucleotídeo Único , Fator de Crescimento Transformador beta1/genética , Idoso , Comorbidade , Diabetes Mellitus/epidemiologia , Feminino , Frequência do Gene , Genótipo , Haplótipos , Humanos , Desequilíbrio de Ligação , Masculino , México/epidemiologia , Pessoa de Meia-Idade , Isquemia Miocárdica/epidemiologia , Fatores de RiscoRESUMO
BACKGROUND: Transforming growth factor-ß1 (TGF-ß1) may be implicated in the development of Chagas heart disease. However, the clinical value of TGF-ß1 measurement is yet to be determined. METHODS: We retrospectively analyzed the outcome of 54 Chagas disease patients without heart failure and with left ventricular (LV) ejection fraction >45% whose TGF-ß1 serum values were determined between January 1998 and December 1999. Primary end point was all-cause mortality and secondary end point was the combination of all-cause mortality or hospitalization due to worsening heart failure or cardiac arrhythmias. RESULTS: TGF-ß1 was independently associated with the occurrence of the primary and secondary end points. The optimal cutoff for TGF-ß1 to identify the primary end point was 12.9 ng/ml (area under the curve = 0.82, p = 0.004, sensitivity 100%, and specificity 57%) and to identify the secondary end point was 30.8 ng/ml (area under the curve = 0.72, p = 0.03, sensitivity 60%, and specificity 86%). LV ejection fraction and LV end-diastolic diameter were also independent predictors of the primary and secondary endpoints, respectively. CONCLUSION: The described association between TGF-ß1 and clinical outcome provides evidence towards the clinical value of TGF-ß1 in Chagas disease.